Targeting ADAM-mediated ligand cleavage to inhibit HER3 and EGFR pathways in non-small cell lung cancer.

We describe here the existence of a heregulin-HER3 autocrine loop, and the contribution of heregulin-dependent, HER2-mediated HER3 activation to gefitinib insensitivity in non-small cell lung cancer (NSCLC). ADAM17 protein, a major ErbB ligand sheddase, is upregulated in NSCLC and is required not only for heregulin-dependent HER3 signaling, but also for EGFR ligand-dependent signaling in NSCLC cell lines. A selective ADAM inhibitor, INCB3619, prevents the processing and activation of multiple ErbB ligands, including heregulin. In addition, INCB3619 inhibits gefitinib-resistant HER3 signaling and enhances gefitinib inhibition of EGFR signaling in NSCLC. These results show that ADAM inhibition affects multiple ErbB pathways in NSCLC and thus offers an excellent opportunity for pharmacological intervention, either alone or in combination with other drugs.

Bicycling crash circumstances vary by route type: a cross-sectional analysis.

BACKGROUND: Widely varying crash circumstances have been reported for bicycling injuries, likely because of differing bicycling populations and environments. We used data from the Bicyclists' Injuries and the Cycling Environment Study in Vancouver and Toronto, Canada, to describe the crash circumstances of people injured while cycling for utilitarian and leisure purposes. We examined the association of crash circumstances with route type. METHODS: Adult cyclists injured and treated in a hospital emergency department described their crash circumstances. These were classified into major categories (collision vs. fall, motor vehicle involved vs. not) and subcategories. The distribution of circumstances was tallied for each of 14 route types defined in an earlier analysis. Ratios of observed vs. expected were tallied for each circumstance and route type combination. RESULTS: Of 690 crashes, 683 could be characterized for this analysis. Most (74%) were collisions. Collisions included those with motor vehicles (34%), streetcar (tram) or train tracks (14%), other surface features (10%), infrastructure (10%), and pedestrians, cyclists, or animals (6%). The remainder of the crashes were falls (26%), many as a result of collision avoidance manoeuvres. Motor vehicles were involved directly or indirectly with 48% of crashes. Crash circumstances were distributed differently by route type, for example, collisions with motor vehicles, including "doorings", were overrepresented on major streets with parked cars. Collisions involving streetcar tracks were overrepresented on major streets. Collisions involving infrastructure (curbs, posts, bollards, street furniture) were overrepresented on multiuse paths and bike paths. CONCLUSIONS: These data supplement our previous analyses of relative risks by route type by indicating the types of crashes that occur on each route type. This information can guide municipal engineers and planners towards improvements that would make cycling safer.

COVID-19 vaccine reactogenicity among participants enrolled in the GENCOV study.

BACKGROUND: GENCOV is a prospective, observational cohort study of COVID-19-positive adults. Here, we characterize and compare side effects between COVID-19 vaccines and determine whether reactogenicity is exacerbated by prior SARS-CoV-2 infection. METHODS: Participants were recruited across Ontario, Canada. Participant-reported demographic and COVID-19 vaccination data were collected using a questionnaire. Multivariable logistic regression was performed to assess whether vaccine manufacturer, type, and previous SARS-CoV-2 infection are associated with reactogenicity. RESULTS: Responses were obtained from n = 554 participants. Tiredness and localized side effects were the most common reactions across vaccine doses. For most participants, side effects occurred and subsided within 1-2 days. Recipients of Moderna mRNA and AstraZeneca vector vaccines reported reactions more frequently compared to recipients of a Pfizer-BioNTech mRNA vaccine. Previous SARS-CoV-2 infection was independently associated with developing side effects. CONCLUSIONS: We provide evidence of relatively mild and short-lived reactions reported by participants who have received approved COVID-19 vaccines.

Imprecision of high-sensitivity cardiac troponin assays at the female 99th-percentile.

BACKGROUND: An analytical benchmark for high-sensitivity cardiac troponin (hs-cTn) assays is to achieve a coefficient of variation (CV) of ≤ 10.0 % at the 99th percentile upper reference limit (URL) used for the diagnosis of myocardial infarction. Few prospective multicenter studies have evaluated assay imprecision and none have determined precision at the female URL which is lower than the male URL for all cardiac troponin assays. METHODS: Human serum and plasma matrix samples were constructed to yield hs-cTn concentrations near the female URLs for the Abbott, Beckman, Roche, and Siemens hs-cTn assays. These materials were sent (on dry ice) to 35 Canadian hospital laboratories (n = 64 instruments evaluated) participating in a larger clinical trial, with instructions for storage, handling, and monthly testing over one year. The mean concentration, standard deviation, and CV for each instrument type and an overall pooled CV for each manufacturer were calculated. RESULTS: The CVs for all individual instruments and overall were ≤ 10.0 % for two manufacturers (Abbott CVpooled = 6.3 % and Beckman CVpooled = 7.0 %). One of four Siemens Atellica instruments yielded a CV > 10.0 % (CVpooled = 7.7 %), whereas 15 of 41 Roche instruments yielded CVs > 10.0 % at the female URL of 9 ng/L used worldwide (6 cobas e411, 1 cobas e601, 4 cobas e602, and 4 cobas e801) (CVpooled = 11.7 %). Four Roche instruments also yielded CVs > 10.0 % near the female URL of 14 ng/L used in the United States (CVpooled = 8.5 %). CONCLUSIONS: The number of instruments achieving a CV ≤ 10.0 % at the female 99th-percentile URL varies by manufacturer and by instrument. Monitoring assay precision at the female URL is necessary for some assays to ensure optimal use of this threshold in clinical practice.

Comparing the effects of infrastructure on bicycling injury at intersections and non-intersections using a case-crossover design.

BACKGROUND: This study examined the impact of transportation infrastructure at intersection and non-intersection locations on bicycling injury risk. METHODS: In Vancouver and Toronto, we studied adult cyclists who were injured and treated at a hospital emergency department. A case-crossover design compared the infrastructure of injury and control sites within each injured bicyclist's route. Intersection injury sites (N=210) were compared to randomly selected intersection control sites (N=272). Non-intersection injury sites (N=478) were compared to randomly selected non-intersection control sites (N=801). RESULTS: At intersections, the types of routes meeting and the intersection design influenced safety. Intersections of two local streets (no demarcated traffic lanes) had approximately one-fifth the risk (adjusted OR 0.19, 95% CI 0.05 to 0.66) of intersections of two major streets (more than two traffic lanes). Motor vehicle speeds less than 30 km/h also reduced risk (adjusted OR 0.52, 95% CI 0.29 to 0.92). Traffic circles (small roundabouts) on local streets increased the risk of these otherwise safe intersections (adjusted OR 7.98, 95% CI 1.79 to 35.6). At non-intersection locations, very low risks were found for cycle tracks (bike lanes physically separated from motor vehicle traffic; adjusted OR 0.05, 95% CI 0.01 to 0.59) and local streets with diverters that reduce motor vehicle traffic (adjusted OR 0.04, 95% CI 0.003 to 0.60). Downhill grades increased risks at both intersections and non-intersections. CONCLUSIONS: These results provide guidance for transportation planners and engineers: at local street intersections, traditional stops are safer than traffic circles, and at non-intersections, cycle tracks alongside major streets and traffic diversion from local streets are safer than no bicycle infrastructure.

Hospital admission from the emergency department for selected emergent diagnoses during the first year of the COVID-19 pandemic in Ontario: a retrospective population-based study.

BACKGROUND: Avoidance of care during the pandemic may have contributed to delays in care, and as a result, worse patient outcomes. We evaluated markers of illness acuity on presentation to the emergency department among patients with non-COVID-19-related emergent diagnoses and associated outcomes. METHODS: We conducted a retrospective study using linked administrative data from Ontario. We selected 4 emergent diagnoses, namely appendicitis, ectopic pregnancy, renal failure and diabetic ketoacidosis. We used the nonemergent diagnosis of cellulitis as a control. Our primary outcome of interest was hospital admission. Secondary outcomes were ambulance arrival, surgical intervention, subsequent hospital admission within 30 days of discharge from the emergency department or hospital and 30-day mortality. We compared outcomes during the first year of the COVID-19 pandemic (Mar. 15-Dec. 31, 2020) with a control period (Mar. 15-Dec. 31, 2018, and Mar. 15-Dec. 31, 2019). RESULTS: Emergency department visits for all conditions initially decreased during the pandemic. During this period, patients across all study diagnoses were more likely to arrive to the emergency department via ambulance. Patients with an ectopic pregnancy had higher odds of surgery in the pandemic period (odds ratio [OR] 1.27, 95% confidence interval [CI] 1.04-1.55) but this was not observed among patients with appendicitis. Patients with renal failure had increased odds of hospital admission (OR 1.14, 95% CI 1.04-1.24) and 30-day mortality (OR 1.17, 95% CI 1.04-1.31) during the pandemic period. INTERPRETATION: The pandemic period was associated with increased arrival to the emergency department via ambulance across all study diagnoses. Although patients with renal failure had increased hospital admission and death, and patients with ectopic pregnancy had an increased risk of surgery, there were no differences in outcomes for other populations, suggesting the health care system was able to care for these patients effectively.

Public knowledge of SARS-CoV-2 serological and viral lineage laboratory testing and result interpretation: A GENCOV study cross-sectional survey.

OBJECTIVES: Concepts related to SARS-CoV-2 laboratory testing and result interpretation can be challenging to understand. A cross-sectional survey of COVID-19 positive adults residing in Ontario, Canada was conducted to explore how well people understand SARS-CoV-2 laboratory tests and their associated results. DESIGN AND METHODS: Participants were recruited through fliers or by prospective recruitment of outpatients and hospitalized inpatients with COVID-19. Enrolled participants included consenting adults with a positive SARS-CoV-2 polymerase chain reaction test result. An 11-item questionnaire was developed by researchers, nurses, and physicians in the study team and was administered online between April 2021 to May 2022 upon enrolment into the study. RESULTS: Responses were obtained from 940 of 1106 eligible participants (85% participation rate). Most respondents understood 1) that antibody results should not influence adherence to social distancing measures (n = 602/888, 68%), 2) asymptomatic SARS-CoV-2 infection following test positivity (n = 698/888, 79%), 3) serological test sensitivity in relation to post-infection timeline (n = 540/891, 61%), and 4) limitations of experts' knowledge related to SARS-CoV-2 serology (n = 693/887, 78%). Conversely, respondents demonstrated challenges understanding 1) conflicting molecular and serological test results and their relationship with immune protection (n = 162/893, 18%) and 2) the impact of SARS-CoV-2 variants on vaccine effectiveness (n = 235/891, 26%). Analysis of responses stratified by sociodemographic variables identified that respondents who were either: 1) female, 2) more educated, 3) aged 18-44, 4) from a high-income household, or 5) healthcare workers responded expectedly more often. CONCLUSIONS: We have highlighted concepts related to SARS-CoV-2 laboratory tests and associated results which may be challenging to understand. The findings of this study enable us to identify 1) misconceptions related to various SARS-CoV-2 test results, 2) groups of individuals at risk, and 3) strategies to improve people's understanding of their test results.

Characterizing Risk Factors for Hospitalization and Clinical Characteristics in a Cohort of COVID-19 Patients Enrolled in the GENCOV Study.

The GENCOV study aims to identify patient factors which affect COVID-19 severity and outcomes. Here, we aimed to evaluate patient characteristics, acute symptoms and their persistence, and associations with hospitalization. Participants were recruited at hospital sites across the Greater Toronto Area in Ontario, Canada. Patient-reported demographics, medical history, and COVID-19 symptoms and complications were collected through an intake survey. Regression analyses were performed to identify associations with outcomes including hospitalization and COVID-19 symptoms. In total, 966 responses were obtained from 1106 eligible participants (87% response rate) between November 2020 and May 2022. Increasing continuous age (aOR: 1.05 [95%CI: 1.01-1.08]) and BMI (aOR: 1.17 [95%CI: 1.10-1.24]), non-White/European ethnicity (aOR: 2.72 [95%CI: 1.22-6.05]), hypertension (aOR: 2.78 [95%CI: 1.22-6.34]), and infection by viral variants (aOR: 5.43 [95%CI: 1.45-20.34]) were identified as risk factors for hospitalization. Several symptoms including shortness of breath and fever were found to be more common among inpatients and tended to persist for longer durations following acute illness. Sex, age, ethnicity, BMI, vaccination status, viral strain, and underlying health conditions were associated with developing and having persistent symptoms. By improving our understanding of risk factors for severe COVID-19, our findings may guide COVID-19 patient management strategies by enabling more efficient clinical decision making.

Route infrastructure and the risk of injuries to bicyclists: a case-crossover study.

OBJECTIVES: We compared cycling injury risks of 14 route types and other route infrastructure features. METHODS: We recruited 690 city residents injured while cycling in Toronto or Vancouver, Canada. A case-crossover design compared route infrastructure at each injury site to that of a randomly selected control site from the same trip. RESULTS: Of 14 route types, cycle tracks had the lowest risk (adjusted odds ratio [OR] = 0.11; 95% confidence interval [CI] = 0.02, 0.54), about one ninth the risk of the reference: major streets with parked cars and no bike infrastructure. Risks on major streets were lower without parked cars (adjusted OR = 0.63; 95% CI = 0.41, 0.96) and with bike lanes (adjusted OR = 0.54; 95% CI = 0.29, 1.01). Local streets also had lower risks (adjusted OR = 0.51; 95% CI = 0.31, 0.84). Other infrastructure characteristics were associated with increased risks: streetcar or train tracks (adjusted OR = 3.0; 95% CI = 1.8, 5.1), downhill grades (adjusted OR = 2.3; 95% CI = 1.7, 3.1), and construction (adjusted OR = 1.9; 95% CI = 1.3, 2.9). CONCLUSIONS: The lower risks on quiet streets and with bike-specific infrastructure along busy streets support the route-design approach used in many northern European countries. Transportation infrastructure with lower bicycling injury risks merits public health support to reduce injuries and promote cycling.

Selective inhibition of JAK1 and JAK2 is efficacious in rodent models of arthritis: preclinical characterization of INCB028050.

Inhibiting signal transduction induced by inflammatory cytokines offers a new approach for the treatment of autoimmune diseases such as rheumatoid arthritis. Kinase inhibitors have shown promising oral disease-modifying antirheumatic drug potential with efficacy similar to anti-TNF biologics. Direct and indirect inhibition of the JAKs, with small molecule inhibitors like CP-690,550 and INCB018424 or neutralizing Abs, such as the anti-IL6 receptor Ab tocilizumab, have demonstrated rapid and sustained improvement in clinical measures of disease, consistent with their respective preclinical experiments. Therefore, it is of interest to identify optimized JAK inhibitors with unique profiles to maximize therapeutic opportunities. INCB028050 is a selective orally bioavailable JAK1/JAK2 inhibitor with nanomolar potency against JAK1 (5.9 nM) and JAK2 (5.7 nM). INCB028050 inhibits intracellular signaling of multiple proinflammatory cytokines including IL-6 and IL-23 at concentrations <50 nM. Significant efficacy, as assessed by improvements in clinical, histologic and radiographic signs of disease, was achieved in the rat adjuvant arthritis model with doses of INCB028050 providing partial and/or periodic inhibition of JAK1/JAK2 and no inhibition of JAK3. Diminution of inflammatory Th1 and Th17 associated cytokine mRNA levels was observed in the draining lymph nodes of treated rats. INCB028050 was also effective in multiple murine models of arthritis, with no evidence of suppression of humoral immunity or adverse hematologic effects. These data suggest that fractional inhibition of JAK1 and JAK2 is sufficient for significant activity in autoimmune disease models. Clinical evaluation of INCB028050 in RA is ongoing.

Personal and trip characteristics associated with safety equipment use by injured adult bicyclists: a cross-sectional study.

BACKGROUND: The aim of this study was to estimate use of helmets, lights, and visible clothing among cyclists and to examine trip and personal characteristics associated with their use. METHODS: Using data from a study of transportation infrastructure and injuries to 690 adult cyclists in Toronto and Vancouver, Canada, we examined the proportion who used bike lights, conspicuous clothing on the torso, and helmets on their injury trip. Multiple logistic regression was used to examine associations between personal and trip characteristics and each type of safety equipment. RESULTS: Bike lights were the least frequently used (20% of all trips) although they were used on 77% of trips at night. Conspicuous clothing (white, yellow, orange, red) was worn on 33% of trips. Helmets were used on 69% of trips, 76% in Vancouver where adult helmet use is required by law and 59% in Toronto where it is not. Factors positively associated with bike light use included night, dawn and dusk trips, poor weather conditions, weekday trips, male sex, and helmet use. Factors positively associated with conspicuous clothing use included good weather conditions, older age, and more frequent cycling. Factors positively associated with helmet use included bike light use, longer trip distances, hybrid bike type, not using alcohol in the 6 hours prior to the trip, female sex, older age, higher income, and higher education. CONCLUSIONS: In two of Canada's largest cities, helmets were the most widely used safety equipment. Measures to increase use of visibility aids on both daytime and night-time cycling trips may help prevent crashes.

Birth cohort hepatitis C antibody prevalence in real-world screening settings in Ontario.

Background: Widespread screening and treatment of hepatitis C virus (HCV) is required to decrease late-stage liver disease and liver cancer. Clinical practice guidelines and Canadian Task Force on Preventative Health Care recommendations differ on the value of one-time birth cohort (1945-75) HCV screening in Canada. To assess the utility of this approach, we conducted a real-world analysis of HCV antibody (Ab) prevalence among birth cohort individuals seen in different clinical contexts. Methods: Cross-sectional study of individuals born between 1945 and 1975 who completed HCV Ab testing at multiple participating centres in Ontario, Canada between January 2016 and December 2020. Differences in prevalence were compared by year of birth, gender, and setting. Results: Among 16,672 birth cohort individuals tested, HCV Ab prevalence was 3.2%. Prevalence was higher among younger individuals which increased from 0.9% among those born between 1945 and 1956 to 4.6% among those born between 1966 and 1975. Prevalence was higher among males (4.4%) compared with females (2.0%) and differed by test site. In primary care, the prevalence was 0.5%, whereas the prevalence was highest among those tested at drug treatment centres (28.7%) and through community outreach (14.0%). Conclusions: HCV Ab prevalence remains high in the 1945-1975 birth cohort. These data highlight the need to re-evaluate existing Canadian Preventative Task Force recommendations, to consider incorporating one-time birth cohort and/or other population-based approaches to HCV screening into the clinical workflow as a preventative health measure, and to increase training among community providers to screen for and treat HCV.

A multifaceted primary care practice-based intervention to reduce ED visits and hospitalization for complex medical patients: A mixed methods study.

BACKGROUND: The management of complex, multi-morbid patients is challenging for solo primary care providers (PCPs) with limited access to resources. The primary objective of the intervention was to reduce the overall rate of Emergency Department (ED) visits among patients in participating practices. METHODS AND FINDINGS: An interrupted time series design and qualitative interviews were used to evaluate a multifaceted intervention, SCOPE (Seamless Care Optimizing the Patient Experience), offered to solo PCPs whose patients were frequent users of the ED. The intervention featured a navigation hub (nurse, homecare coordinator) to link PCPs with hospital and community resources, a general internist on-call to provide phone advice or urgent assessments, and access to patient results on-line. Continuous quality improvement (QI) strategies were employed to optimize each component of the intervention. The primary outcome was the relative pre-post intervention change in ED visit rate for patients of participating practices compared with that for a propensity-matched control group of physicians over the contemporaneous period. Themes were identified from semi-structured interviews on PCP's experiences and influential factors in their engagement. Twenty-nine physicians agreed to participate and were provided access to the intervention over an 18-month time period. There were a total of 1,525 intervention contacts over the 18-months (average: 50.6±60.8 per PCP). Both intervention and control groups experienced a trend towards lower rates of ED use by their patients over the study time period. The pre-post difference in trend for the intervention group compared to the controls was not significant at 1.4% per year (RR = 1.014; p = 0.59). Several themes were identified from qualitative interviews including: PCPs felt better supported in the care of their patients; they experienced a greater sense of community, and; they were better able to provide shared primary-specialty care. CONCLUSIONS: This multifaceted intervention to support solo PCPs in the management of their complex patients did not result in a reduced rate of ED visits compared to controls, likely related to variable uptake among PCPs. It did however result in more comprehensive and coordinated care for their patients. Future directions will focus on increasing uptake by improving ease of use, increasing the range of services offered and expanding to a larger number of PCPs.

Selective inhibition of ADAM metalloproteases as a novel approach for modulating ErbB pathways in cancer.

PURPOSE: ErbB receptor signaling pathways are important regulators of cell fate, and their dysregulation, through (epi)genetic alterations, plays an etiologic role in multiple cancers. ErbB ligands are synthesized as membrane-bound precursors that are cleaved by members of the ADAM family of zinc-dependent metalloproteases. This processing, termed ectodomain shedding, is essential for the functional activation of ErbB ligands. Recent studies suggest that elevated levels of ErbB ligands may circumvent the effectiveness of ErbB-targeted therapeutics. Here, we describe the discovery and preclinical development of potent, selective inhibitors of ErbB ligand shedding. EXPERIMENTAL DESIGN: A series of biochemical and cell-based assays were established to identify selective inhibitors of ErbB ligand shedding. The therapeutic potential of these compounds was assessed in multiple in vivo models of cancer and matrix metalloprotease-related toxicity. RESULTS: INCB3619 was identified as a representative selective, potent, orally bioavailable small-molecule inhibitor of a subset of ADAM proteases that block shedding of ErbB ligands. Administration of INCB3619 to tumor-bearing mice reduced ErbB ligand shedding in vivo and inhibited ErbB pathway signaling (e.g., phosphorylation of Akt), tumor cell proliferation, and survival. Further, INCB3619 synergized with clinically relevant cancer therapeutics and showed no overt or compounding toxicities, including fibroplasia, the dose-limiting toxicity associated with broad-spectrum matrix metalloprotease inhibitors. CONCLUSIONS: Inhibition of ErbB ligand shedding offers a potentially novel and well-tolerated therapeutic strategy for the treatment of human cancers and is currently being evaluated in the clinic.

Selective inhibition of ADAM metalloproteases blocks HER-2 extracellular domain (ECD) cleavage and potentiates the anti-tumor effects of trastuzumab.

The HER-2 receptor tyrosine kinase is an important regulator of cell proliferation and survival, and it is a clinically validated target of therapeutic intervention for HER-2 positive breast cancer patients. Its extracellular domain (ECD) is frequently cleaved by protease(s) in HER-2 overexpressing breast cancer patients, rendering the remaining membrane-bound portion (p95) a constitutively activated kinase. The presence of both serum ECD and cellular p95 protein has been linked to poor clinical outcome as well as reduced effectiveness of some therapeutic treatments. We have identified a series of potent, selective small molecule inhibitors of ADAM proteases, exemplified here by INCB003619, and demonstrate that these inhibitors effectively block HER-2 cleavage in HER-2 overexpressing human breast cancer cell lines. Intriguingly, when used in combination, INCB003619 dramatically enhances the antiproliferative activity of suboptimal doses of the anti-HER-2 antibody, trastuzumab, in HER-2 overexpressing/shedding breast cancer cell lines, accompanied by reduced ERK and AKT phosphorylation. Furthermore, INCB003619, in combination with trastuzumab, augments the pro-apoptotic and antiproliferative effects of the chemotherapeutic agent paclitaxel. Consistent with these in vitro data, INCB003619 reduces serum ECD levels and enhances the antitumor effect of trastuzumab in a xenograft tumor model derived from the HER-2 overexpressing BT-474 breast cancer cell line. Collectively, these findings suggest that blocking HER-2 cleavage with selective ADAM inhibitors may represent a novel therapeutic approach for treating HER-2 overexpressing breast cancer patients.

Severity of urban cycling injuries and the relationship with personal, trip, route and crash characteristics: analyses using four severity metrics.

OBJECTIVE: To examine the relationship between cycling injury severity and personal, trip, route and crash characteristics. METHODS: Data from a previous study of injury risk, conducted in Toronto and Vancouver, Canada, were used to classify injury severity using four metrics: (1) did not continue trip by bike; (2) transported to hospital by ambulance; (3) admitted to hospital; and (4) Canadian Triage and Acuity Scale (CTAS). Multiple logistic regression was used to examine associations with personal, trip, route and crash characteristics. RESULTS: Of 683 adults injured while cycling, 528 did not continue their trip by bike, 251 were transported by ambulance and 60 were admitted to hospital for further treatment. Treatment urgencies included 75 as CTAS=1 or 2 (most medically urgent), 284 as CTAS=3, and 320 as CTAS=4 or 5 (least medically urgent). Older age and collision with a motor vehicle were consistently associated with increased severity in all four metrics and statistically significant in three each (both variables with ambulance transport and CTAS; age with hospital admission; and motor vehicle collision with did not continue by bike). Other factors were consistently associated with more severe injuries, but statistically significant in one metric each: downhill grades; higher motor vehicle speeds; sidewalks (these significant for ambulance transport); multiuse paths and local streets (both significant for hospital admission). CONCLUSIONS: In two of Canada's largest cities, about one-third of the bicycle crashes were collisions with motor vehicles and the resulting injuries were more severe than in other crash circumstances, underscoring the importance of separating cyclists from motor vehicle traffic. Our results also suggest that bicycling injury severity and injury risk would be reduced on facilities that minimise slopes, have lower vehicle speeds, and that are designed for bicycling rather than shared with pedestrians.

Inhibition of factor Xa reduces ischemic brain damage after thromboembolic stroke in rats.

BACKGROUND AND PURPOSE: Factor Xa (FXa) is a key coagulation protease and target for novel antithrombotic agents for prevention and treatment of diverse thromboembolic disorders. In the present study we describe the effect of a novel, potent, and selective FXa inhibitor, DPC602, on brain damage and neurobehavioral consequence in a rat thromboembolic model of stroke. METHODS: Thromboembolic stroke was induced in rats by placement of an autologous clot into the middle cerebral artery. RESULTS: Laser-Doppler monitoring of cerebral blood flow demonstrated that DPC602 (8 mg/kg, single IV/IP bolus pretreatment) markedly improved cerebral blood flow after thromboembolic stroke by 25% to 160% (n=6; P<0.001) at 1 to 6 hours. DPC602 demonstrated concentration- and time-dependent reductions in infarct size, with maximal effect (89% reduction; n=14; P<0.001) at the highest dose over controls. Neurological function was also significantly improved in DPC602-treated rats at days 1, 3, and 7 (n=13; P<0.01). DPC602 treatment did not cause cerebral hemorrhage, assessed by free hemoglobin in the ischemic brain tissues. CONCLUSIONS: These data suggest that anticoagulation with a selective FXa inhibitor might ameliorate the extent of ischemic brain damage and neurological deficits after a thromboembolic event. Enhanced clot dissolution and early reperfusion may account for the cerebrovascular-protective effect of the drug.

Inhibition of Fas-mediated apoptosis by antigen: implications for lymphomagenesis.

Apoptotic deletion of expanded B cell populations is essential in avoidance of autoimmune disease and immune regulation of some B cell malignancies. The role of CD4+ T cells in B cell apoptosis is evident from the high incidence of B cell tumors and autoimmunity in patients with T cell diseases such as the acquired immune deficiency syndrome (AIDS). We have previously demonstrated that in Epstein-Barr Virus (EBV) negative Burkitt's lymphoma (BL), a tumor derived from proliferating centroblasts of the germinal center, the malignant lymphocytes can be induced to express Fas (CD95) by ligation of CD40 at the B cell surface. Upon CD40 engagement, BL cells are sensitized to T-cell derived death signals provided by Fas ligand (FasL, CD95L). HBL-3 is a cell line derived from an AIDS-related BL in which the tumor IgM binds the human erythrocyte "i" antigen. To determine whether Fas-mediated apoptosis of BL cells is reduced in the context of antigen to which the tumor IgM binds, we stimulated HBL-3 cells with CD40 ligand (CD40L, CD154) in the presence and absence of human erythrocytes expressing the "i" antigen, and measured Fas-mediated apoptosis upon exposure to an agonistic anti-Fas antibody. We observed that HBL-3 cells were sensitized to Fas-mediated death by exposure to CD40L. When i+ RBCs were present, Fas-mediated apoptosis in HBL-3 cells was reduced by greater than 30%. In contrast, there was no reduction in Fas-mediated apoptosis in the presence of i- (I+) RBCs. These findings demonstrate that Fas-mediated deletion of BL cells is inhibited upon surface IgM engagement by antigen for which the malignant clone has affinity.